p53 Deficiency Sensitizes Clonogenic Cells to Irradiation in the Large but Not the Small Intestine

The role of p53 in the survival of irradiated crypts in the small intestine and three regions of the large intestine (cecum, mid-colon and rectum) was assessed by comparing the responses in p53 null, p53 heterozygous and wild-type mice. There was no difference in the levels of crypt survival in the small intestine between the three genotypes, although the rate of cell depletion and regeneration in the null mice appeared slower. In the large intestine, crypt survival was lowest in the null mice compared to the other genotypes, in particular after high doses. The levels of crypt survival in the heterozygotes were not significantly different from those in the wild-type mice. Hence the greater radioresistance of crypts in the colon than in the small intestine, reported previously by us and others using various other mouse strains, may be partly attributable to the presence of p53. This effect is not readily explained by current knowledge concerning the decreased p53 expression and the greater expression of the survival gene Bcl2 in the stem cell zone of crypts in the colon compared to those in the small intestine. Reduced repair associated with the lack of a G₂-phase checkpoint delay, the predominant arrest point for intestinal cells, is a possible explanation for the decrease in survival.